21-fluoro-17alpha-methylpregnane derivatives



United'States, Patent 6 Claims. 01. 260-43955) This invention relates to orally active progestational agents, to methods for their preparation, and to intermediates used in the preparation thereof. More specifically, our invention relates to progestationally-active 21-fluoro-17u-methyl-steroids of the pregnane series, some of which are characterized further by carrying additional substituents in position 6, preferably halogen or lower alkyl groups, and some of which may also possess double bonds in positions 4 and 6. It alsorelates to intermedi- 'a tes useful in the preparation of the new progestationallyactive steroid compounds.

Generically, the biologically active compounds of the present invention include the compounds of the following general structural formula in which (1) Ris methyl in the alpha position and Z represents a single bond or (2) R is methyl and Z represents a double bond or (3) R isfluorine in the alpha position and Z represents 3 a single bond.

a sazzs Patented Ma 11', 1 965 For intramuscular administration, the compounds of this invention are employed in solution in a pharmaceutically acceptable solvent, such as, for example, a vegetable of this invention may be administered in dosage forms such as, for example, tablets or capsules, formulated with a pharmaceutically acceptable carrier, for example, with excipients such as lactose, starch, magnesium stearate, and the like, the individual dosage forms preferably to contain from 5-5O mg. of the active compound.

oil, preferably in dosages of from 10-50 gm. per injection, and for subcutaneous administration, it is convenient to use aqueous suspensions preferably containing from 1050 mg. of the active compound per millilitre.

A preferred method for the preparation of the compounds of our invention comprises the following steps:

17a.-methylpregnenolone (I) is condensed with diethyloxalate in dry ethanol and in the presence of sodium ethoxide to obtain 17a-rnethyl-2l-ethoxalylpregnenolone (II). Treatment of the sodium salt of the latter compound with perchloryl fluoride in dry methanol, followed by treatment with potassium acetate to cleave the ethoxalyl side chain results in 2l-fluoro-l7a-methylpregnen olone (III). The latter compound is epoxidized with an epoxidizing agent, for example, peracetic acid, to yield the corresponding 5u,6a-epoxide (IV )lwhich is acetylated in the conventional manner to give the corresponding 3-acetate, 3,8-acet0xy-21-fiuoro-17a-methyl 5a,6zx-0Xld0- pregnan-ZO-one (V), which in turn treated with a methyl magnesium halide in an inert solvent at a temperature below 35 0., preferably with methyl magnesium bromide in ether solution at room temperature, to yield smoothly 3,B,5ot-dihydroxy 6,8,17a dimethyl-2l-fluoropregnan-20- one (VI). Alternatively, the same compound VI may also be prepared by treatment of the epoxide IV with a methyl magnesium halide in an inert solvent at a temperature below 35 C., preferably with methyl magnesium bromide in ether solution at room temperature. The *dihydroxylated compound VI is oxidized with hexavalent chromium ion, preferably in acetone solution with chromic acid, to yield 2l-fiuoro-6B,17a-dimethyl 5oz hydroxypregnane- 3,20-dione (VII), which is in turn treated to eliminate the elements of water with concomitant inversion of configuration at carbon atom 6, preferably with sodium hydroxide in methanol, to yield 6a,17a-dimethyl-2l-fiuoroprogesterone (VIII). Dehydrogenation of the latter compound with chloranil in the conventionalrmanner yields 2l-fluoro-6-dehydro-6, 17 ot-dimethylprogesterone (IX) As a second alternative in our syntheses of 21-fiuoro- 17u-methyl-steroids of the pregnane series, BIB-acetoxy- 2l-fiuoro-l7-a-methyl-5a,6u-oxidopregnan-20-one (V), is treated with anhydrous hydrogen fluoride to yield the corresponding fluorohydrin, 3B-acetoxy-6;8,21-difluoro-5ahydroxy-17a-methyl-pregnan-20-one (X), which is in turn hydrolyzed with a strong mineral acid such as, e.g., perchloric acid in methanol solution, to yield 6fl,2l-difluoro- 3fi,5a-dihydroxy-ITa-methylpregnan-ZO- one (XI). The latter dihydroxylated compound XI is then oxidized in the conventional manner with hexavalent chromium ion, preferably with chromic acid in acetone solution, to yield the corresponding 3,20-diketone, 66, 21-difluoro-5a-hydroxy-l7a-methylpregnane-3,ZO-dione (XII), from which I 3 intermediates, and in which compounds VIII, IX and XIII are progestationally active.

on, CH COCOOEt;

=0 :'---o1r3 l om i l HO HO CIJHZF Z1121 0:0 :0 l L- CH3 jHCHs i i HO noi I IV 111 '0" CH2]? EH21? :0 :0 i I Cm "CH3 i I ACO HO 5 V E b OII R VI. R=OH3 l XI. R=F ZHzF EH21 :0 :0 I on, i on,

o= c X C: VII. 3:011.

; i XII. R=F 0H F t! OH R CHZF 011m :0 IE=O The following examples are illustrative of our invention.

Example 1 Cir hours and then left standing at room temperature overnight. After thirty minutes of heating a heavy precipitate forms. The precipitate is filtered and washed with ethanol and ether. The salt is then suspended in ether and enough hydrochloric acid is added to dissolve the solid. The ether is washed free of acid, dried and evaporated to dryness, leaving a colorless solid M.P. 126- 128 C. Crystallization of a sample gives pure 21-ethoxalyl-17a-methylpregnenolone II), M.P. 137139 C. max.=291 m 5:8,930.

Example 2 To sodium methoxide, prepared from 2.65 g. of sodium and 200 cc. of methanol, 200 cc. of ether are added, followed by 14.5 g. of 2l-ethoxallyl-l7u-methylpregnenolone (II) dissolved in 315 cc. of methanol and 440 cc. of ether. Soon after the beginning of the addition a precipitate forms. Stirring is continued for two hours at room temperature. The salt is filtered, washed with ether and dried.

A suspension of 3.08 g. of the above salt in cc. of dry methanol is cooled to -15 to -13 C. Perchloryl fluoride is bubbled through the above suspension for ten minutes, then the cooling bath is removed and the reaction is permitted to proceed at the temperature of a tap water bath until the solution is neutral. The solution at this point is homogeneous. Two-thirds of the volume is evaporated under vacuum and the residue is refiuxed for six hours with 6 g. of potassium acetate. After standing overnight at room temperature the mixture is poured into water, and extracted with ether.

practically colorless solid, M.P. 195-199 C. The infrared spectrum shows OH bands and a carbonyl band at 1720 cm.- characteristic of a 21-fluoro-17a-methyl-20- ketone, in agreement with the spectrum expected for 21- fluoro-l7a-methylpregnenolone (HI).

Example 3 with pyridine (50 cc.) and acetic anhydride (10 cc.)

overnight at room temperature to give Bfi-acetoxy-Zlfiuoro-17et-methyl-5a,6ot-epoxypregnane-20-one (V), M.P. 2l3-217 C. (from methanol).

Example 4 To a quantity of the epoxide (V) (1.730 g.) in

ml. dry benzene, there was added, at 10-15 C., 36 ml. of a 3 M solution of methyl magnesium bromide in ether. The mixture was stirred at room temperature for sevenorganic layer to neutrality gave, upon evaporation, 1.93 g. of 313,50: dihydroxy-6,B,17a-dimethy1-21-fiuoropregnan-20-one (VI) as an amorphous product characterized by its LR. absorption spectrum showing bands at 3620 cmr 3450 cm.'" and 1716 cmr Alternatively, 7.88 g. of the epoxide IV dissolved in 565 ml. dry benzene and ml. of a 3 M solution of methyl magnesium bromide in ether were stirred at room temperature for seventeen hours. The resulting mixture was worked up as above to yield 9.3 g. of a yellow oil, identical with the compound VI as obtained above.

The latter compound was oxidized by dissolving it in 100 cc. acetone, with 3 cc. of an 8 N solution of chromic acid at 0 C. The usual working up gave 1.5 g. of 21- fiuoro-GB,17a-dimethyl-5u-hydroxypregnene 3,20 dione (VII), M.P. 220 C.

Example 5 A quantity of 1.75 g. of the'hydroxydiketone (VII) is dissolved in 70 cc. of a 5% sodium hydroxide solution The ether is washed with water, dried, and evaporated, leaving a' teen hours. Extraction with ether and washing of the in methanol and refluxed for fifty minutes in a nitrogen atmosphere. After cooling 2 cc. of acetic acid were added and the mixture taken to dryness, extracted with ether, washed to neutrality and the residue chromatographed over cc. of alumina. Petroleum etherbenzene mixture eluted the product (VII'I), ,17a-dimethyl 2'l-fluoroprogesterone, M.P. 175-177 C. from ether.

Example 6 Example 7 To 6.8 g. of liquid fluorides at 60 C. are added 15.0

cc. of tetrahydrofuran, 6.8 cc. of chloroform, and 6.8 g. of 3p acetoxy-Zl-fluoro-17a-methyl-5a,6a-oxidopregnan-20-one (V) dissolved in 50 cc. of chloroform. The mixture is then left at --10 C. for two hours. The reaction mixture is poured in ice-water containing some ;sodium bicarbonate. The chloroform solution is washed with sodium bicarbonate and water, dried and evaporated,

leaving the crude fluorohydrin (X). The pure 3B-acetow-618,21-difluoro-5a-hydroxy 17a methylpregnan-ZO- one (X) melts at 232 C. with decomposition.

Example 8 Four and one-half grams of the fluorohydrin acetate (X) are dissolved in 175 cc. of hot methanol containing 4.5 cc. of perchloric acid. The solution is left at room temperature overnight. Water is added and the resulting solid is filtered, washed free of acid, and dried. The solid is taken up in ether and the insoluble material is filtered, M.P. 192 C. (dec.). Pure 65,21-difluoro-3B, 5a-dihydroxy-17amethylpregnan-20 one (XI) melts at 198 C. with decomposition.

Example 9 To a solution of 1.6 g. of the diol (XI) in'100 cc. of acetone there is added, at 10 C., 4.03 cc. of an 8 N chromic acid solution. When all of the reagent has been added the mixture is poured in ice-water. The organic com pound is extracted with methylene chloride. The organic solution is washed free of acid, dried, and evaporated to dryness. The solid residue is taken up in ether and the insoluble substance is filtered, M.P. 240 C. (dec.). 65,21 difluoro-Su-hydroxy-17a-methylpregnan- 3,20-dione (XH) melts at 245 C., with decomposition.

Example 10 Dry hydro-gen chloride is passed through an ice-cold suspension of 1 g. of hydroxy-ketone (XH) in 23 cc. of chloroform for one hour. The mixture is then left at 0 C. for an additional hour. The chloroform solution is washed with water, sodium bicarbonate solution, and finally with water. The residue is a solid, M.P. C. (dec.). Crystallization gives pure 6a,21-difluor0- l7amethylprogesterone (XIII), M.P. 196 C. (dec.). The ultra-violet spectrum of compound XIII shows a maximum of absorption at 236 mp with an extinction coefiicient of 17,400. The infra-red spectrum shows a 21- fluoro-17a-methyl-20-carbony1 band at 1717 cmr a conjugated carbonyl band at 1670 cmf and a C=C double bond at 1625 cmr We claim:

1. 6a,2l-difiuoro-l7a-methylprogesterone.

2. 21-fluoro 3,8 hydroxyal7u-methy1 5a,6a-oxidopregnan-ZO-one.

3. 3,9 acetoxy 21 fluoro-17a-methyl-5a,6u-oxidopregnan-ZO-one.

4. 3,8 acetoxy 65,21 difluoro-Sa-hydroxy 17amethyl-pregnan-ZO-one.

5. 66,21 difiuoro-3fi,5a dihydroxy-l7a-methylpregnan-QO-one.

6. 6B,21-difluoro 50c hydroxy-17a-methylpregnane-3, 20-dione.

References Cited by the Examiner UNITED STATES PATENTS 3,042,688 7/62 Camerino et al. 260-397.3 3,133,913 5/64- Deghenghi 260-239.55

FOREIGN PATENTS 882,388 11/61 Great Britain. 883,310 1-1/61 Great Britain.

OTHER REFERENCES Deghenghi et al.: Journal of Med. Chem. vol. 6, May 1963, No. 3, pages 301-304.

LEWIS GOTTS, Primary Examiner.

UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent No. 3,183,228 May 11, 1965 Romano Deghenghi et a1.

It is hereby certified that error appears in the above numbered patent requiring correction and that the said Letters Patent should read as corrected below.

In the grant, line 1, and in the heading to the printed specification, line 4, for "Ontario", each occurrence, read Quebec column 2, line 22, after "which" insert is column 5, line 22, for "fluorides" read fluoride Signed and sealed this 5th day of October 1965.

(SEAL) Allest:

ERNEST W. SWIDER EDWARD J. BRENNER Attesting Officer Commissioner of Patents 

2. 21-FLUORO-3B-HYDROXY-17A-METHYL-5A,6A-OXIDOPREGNAN-20-ONE. 